A Study to Evaluate the Safety and Efficacy of VX-371 in Subjects With Cystic Fibrosis Who Are Homozygous for the F508del-CFTR Mutation

• Sponsor: Parion Sciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02709109
• Collaborator: Vertex Pharmaceuticals Incorporated (Industry)
• Enrollment: 147
• Locations: 40
• Arms: 4
• Duration (Months): 19
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety and efficacy of treatment with VX-371 in hypertonic saline compared to hypertonic saline alone in subjects with cystic fibrosis (CF) who are ≥12 years of age, homozygous for the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) mutation, and being treated with Orkambi

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis	Drug: VX-371 + HS; Drug: Hypertonic saline; Drug: Placebo; Drug: Orkambi; Drug: VX-371	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 147 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2a, Randomized, Double-blind, Placebo-controlled, Incomplete Block, Crossover Study to Evaluate the Safety and Efficacy of VX-371 in Subjects Aged 12 Years or Older With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation, and Being Treated With Orkambi
• Study Start Date: Feb 1, 2016
• Actual Primary Completion Date: Sep 1, 2017
• Actual Study Completion Date: Sep 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sequence 1: VX-371 + Hypertonic Saline (HS), then HS Participants received 85 microgram (mcg) VX-371 diluted in 3 milliliter (mL) 4.2 percent (%) HS through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 milligram (mg)/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their cystic fibrosis (CF) standard of care.	Drug: VX-371 + HS; Drug: Hypertonic saline; Drug: Orkambi; Other Names: lumacaftor/ivacaftor
Experimental: Sequence 2: HS, then VX-371 + HS Participants received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 85 mcg VX-371 diluted in 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care.	Drug: VX-371 + HS; Drug: Hypertonic saline; Drug: Orkambi; Other Names: lumacaftor/ivacaftor
Experimental: Sequence 3: VX-371 + Placebo, then Placebo Participants received 85 mcg VX-371 diluted in 3 mL 0.17% Saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care.	Drug: Placebo; Drug: Orkambi; Other Names: lumacaftor/ivacaftor ; Drug: VX-371
Experimental: Sequence 4: Placebo, then VX-371 + Placebo Participants received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 85 mcg VX-371 diluted in 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care.	Drug: Placebo; Drug: Orkambi; Other Names: lumacaftor/ivacaftor ; Drug: VX-371

Outcome Measures

Primary Outcome Measures

1. Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs [Baseline (Day 1) up to 28 days post last administration of study drug (up to 112 days)]

   An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AEs included abnormal clinically significant findings for spirometry, clinical laboratory parameters, standard 12-lead electrocardiograms (ECGs), vital signs and ophthalmologic examinations. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 112 days (up to 28 days after last dose) that were absent before treatment or that worsened relative to pretreatment state. TEAEs included both serious and non-serious TEAEs.

2. Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 28 [Study baseline, Day 28]

   FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Study Baseline was defined as the most recent non-missing measurement before the first dose of inhaled study drug in the study. Day 28 measurements after treatment discontinuation from the treatment period in which discontinuation occurred were included in the analysis.

Secondary Outcome Measures

1. Plasma Concentrations of VX-371 [Pre-dose (90 minutes prior inhaled study drug administration) and 60 minutes post-dose on Days 1, 14 and 28 within treatment period 1 and 2]

2. Urine Concentrations of VX-371 [Pre-dose (90 minutes prior inhaled study drug administration) and 60 minutes post-dose on Days 1, 14 and 28 within treatment period 1 and 2]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Willing and able to use the delivery device as directed by the study manual.

• Confirmed diagnosis of CF, defined as a sweat chloride value ≥60 mmol/L by quantitative pilocarpine iontophoresis.

• Homozygous for the F508del CFTR mutation. If the CFTR screening genotype result is not received before randomization, a previous CFTR genotype lab report may be used to establish eligibility.

• Percent predicted forced expiratory volume at one second (FEV1) of ≥40 to <90 percentage points adjusted for age, sex, and height according to the Global Lung Initiative (GLI) at the Screening Visit.

• Willing to discontinue physician-prescribed saline use.

• Female subjects of childbearing potential with a negative serum pregnancy test at the Screening Visit.

Exclusion Criteria:

• History of any comorbidity, which in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject.

• Any clinically significant laboratory abnormalities at the Screening Visit that would interfere with the study assessments or pose an undue risk for the subject.

• An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of study drug).

• A 12 lead ECG demonstrating QTcF >450 msec at the Screening Visit.

• History of solid organ or hematological transplantation.

• Used diuretics or renin-angiotensin aldosterone system antihypertensive drugs in the 28 days prior to Screening or an anticipated need for any of these medications during the study.

• Ongoing or prior participation in an investigational drug study within 30 days of the Screening Visit.

• Inability to withhold short-acting, long-acting, or once-daily, long-acting bronchodilator use for 4, 12, or 24 hours prior to clinic visit, respectively.

• History of significant intolerance to inhaled saline, or intolerance to the single dose of saline at Screening

• Known hypersensitivity or history of intolerance to Orkambi.

• Pregnant and nursing females.

• Subjects who have participated in Parion Sciences Study NCT02343445.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Little Rock	Arkansas	United States
2		Oakland	California	United States
3		Gainesville	Florida	United States
4		Miami	Florida	United States
5		Orlando	Florida	United States
6		Chicago	Illinois	United States
7		Glenview	Illinois	United States
8		Kansas City	Kansas	United States
9		New Orleans	Louisiana	United States
10		Worcester	Massachusetts	United States
11		Detroit	Michigan	United States
12		Grand Rapids	Michigan	United States
13		Minneapolis	Minnesota	United States
14		Jackson	Mississippi	United States
15		Lebanon	New Hampshire	United States
16		Albuquerque	New Mexico	United States
17		Albany	New York	United States
18		Hawthorne	New York	United States
19		Syracuse	New York	United States
20		Charlotte	North Carolina	United States
21		Cleveland	Ohio	United States
22		Pittsburgh	Pennsylvania	United States
23		Austin	Texas	United States
24		Dallas	Texas	United States
25		Fort Worth	Texas	United States
26		Tyler	Texas	United States
27		Charlottesville	Virginia	United States
28		Richmond	Virginia	United States
29		Madison	Wisconsin	United States
30		Milwaukee	Wisconsin	United States
31		Bron Cedex		France
32		Pierre-Bénite		France
33		Roscoff Cedex		France
34		Strasbourg Cedex 2		France
35		Dublin		Ireland
36		Birmingham		United Kingdom
37		Bristol		United Kingdom
38		London		United Kingdom
39		Manchester		United Kingdom
40		Southampton		United Kingdom

Sponsors and Collaborators

• Parion Sciences
• Vertex Pharmaceuticals Incorporated

Investigators

• Study Chair: Alison Church, MD, Parion Sciences

Study Documents (Full-Text)

• Study Protocol - Jul 22, 2016
• Statistical Analysis Plan - Jul 27, 2017

More Information

Publications

None provided.

• Responsible Party: Parion Sciences
• ClinicalTrials.gov Identifier: NCT02709109
• Other Study ID Numbers: VX15-371-101; 2015-004841-13
• First Posted: Mar 15, 2016
• Last Update Posted: Jul 29, 2021
• Last Verified: Jul 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis; Ivacaftor

Study Results

Participant Flow

Pre-assignment Detail	Total 147 participants entered in this study, 5 participants discontinued from the study before the randomization. Of which 142 participants were randomized to receive 1 of the 4 treatment sequences: 1) VX-371 + hypertonic saline (HS), Then HS; 2) HS, Then VX-371 + HS; 3) VX-371 + Placebo, Then Placebo; 4) Placebo, Then VX-371 + Placebo.

Arm/Group Title	Sequence 1: VX-371 + HS, Then HS	Sequence 2: HS, Then VX-371 + HS	Sequence 3: VX-371 + Placebo, Then Placebo	Sequence 4: Placebo, Then VX-371 + Placebo
Arm/Group Description	Participants received 85 microgram (mcg) VX-371 diluted in 3 milliliter (mL) 4.2 percent (%) HS through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 milligram (mg)/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their cystic fibrosis (CF) standard of care.	Participants received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 85 mcg VX-371 diluted in 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care.	Participants received 85 mcg VX-371 diluted in 3 mL 0.17% Saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care.	Participants received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 85 mcg VX-371 diluted in 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care.
Period Title: Treatment Period 1 (28 Days)
STARTED	49	47	22	24
COMPLETED	45	42	21	24
NOT COMPLETED	4	5	1	0
Period Title: Treatment Period 1 (28 Days)
STARTED	45	42	21	24
COMPLETED	43	40	18	24
NOT COMPLETED	2	2	3	0
Period Title: Treatment Period 1 (28 Days)
STARTED	43	40	18	24
COMPLETED	41	36	15	24
NOT COMPLETED	2	4	3	0

Baseline Characteristics

Arm/Group Title	Sequence 1: VX-371 + HS, Then HS	Sequence 2: HS, Then VX-371 + HS	Sequence 3: VX-371 + Placebo, Then Placebo	Sequence 4: Placebo, Then VX-371 + Placebo	Total
Arm/Group Description	Participants received 85 mcg VX-371 diluted in 3 milliliter (mL) 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care.	Participants received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 85 mcg VX-371 diluted in 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care.	Participants received 85 mcg VX-371 diluted in 3 mL 0.17% Saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care.	Participants received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 85 mcg VX-371 diluted in 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care.	Total of all reporting groups
Overall Participants	49	47	22	24	142
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	23.6 (9.07)	22.3 (8.75)	26.0 (10.95)	22.1 (7.80)	23.3 (9.08)
Sex: Female, Male (Count of Participants)
Female	21 42.9%	16 34%	7 31.8%	11 45.8%	55 38.7%
Male	28 57.1%	31 66%	15 68.2%	13 54.2%	87 61.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	49 100%	45 95.7%	22 100%	23 95.8%	139 97.9%
Unknown or Not Reported	0 0%	2 4.3%	0 0%	1 4.2%	3 2.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	1 2.1%	0 0%	0 0%	1 0.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%
White	49 100%	45 95.7%	22 100%	23 95.8%	139 97.9%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 2.1%	0 0%	1 4.2%	2 1.4%

Outcome Measures

1. Primary Outcome

Title	Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
Description	An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AEs included abnormal clinically significant findings for spirometry, clinical laboratory parameters, standard 12-lead electrocardiograms (ECGs), vital signs and ophthalmologic examinations. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 112 days (up to 28 days after last dose) that were absent before treatment or that worsened relative to pretreatment state. TEAEs included both serious and non-serious TEAEs.
Time Frame	Baseline (Day 1) up to 28 days post last administration of study drug (up to 112 days)

Outcome Measure Data

Analysis Population Description

Safety set included all participants who received at least 1 dose of inhaled study drug.

Arm/Group Title	VX-371 + Hypertonic Saline	Hypertonic Saline	VX-371 + Placebo	Placebo
Arm/Group Description	Participants received 85 mcg VX-371 diluted in 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.	Participants received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.	Participants received 85 mcg VX-371 diluted in 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.	Participants received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.
Measure Participants	89	90	46	42
Participants With TEAEs	65 132.7%	66 140.4%	32 145.5%	28 116.7%
Participants With Serious TEAEs	8 16.3%	4 8.5%	6 27.3%	3 12.5%

2. Primary Outcome

Title	Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 28
Description	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Study Baseline was defined as the most recent non-missing measurement before the first dose of inhaled study drug in the study. Day 28 measurements after treatment discontinuation from the treatment period in which discontinuation occurred were included in the analysis.
Time Frame	Study baseline, Day 28

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS) included all randomized participants who carried the intended homozygous F508del-cystic fibrosis transmembrane conductance regulator (CFTR) mutation and received at least 1 dose of inhaled study drug. Here, "overall number of participants analyzed" signifies participants evaluable for this outcome measure.

Arm/Group Title	VX-371 + Hypertonic Saline	Hypertonic Saline	VX-371 + Placebo	Placebo
Arm/Group Description	Participants received 85 mcg VX-371 diluted in 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.	Participants received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.	Participants received 85 mcg VX-371 diluted in 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.	Participants received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.
Measure Participants	79	77	43	38
Least Squares Mean (Standard Error) [percentage points]	0.1 (0.8)	-0.1 (0.8)	-0.8 (1.1)	0.8 (1.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VX-371 + Hypertonic Saline, Hypertonic Saline
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8173
	Comments
	Method	Mixed-effects Model for Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) mean difference
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; -1.4 to 1.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Hypertonic Saline, VX-371 + Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5903
	Comments
	Method	Mixed-effects Model for Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.7
	Confidence Interval	(2-Sided) 95%; -3.3 to 1.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	VX-371 + Hypertonic Saline, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5917
	Comments
	Method	Mixed-effects Model for Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.7
	Confidence Interval	(2-Sided) 95%; -3.4 to 1.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Hypertonic Saline, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5021
	Comments
	Method	Mixed-effects Model for Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 95%; -3.6 to 1.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	VX-371 + Placebo, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1382
	Comments
	Method	Mixed-effects Model for Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.6
	Confidence Interval	(2-Sided) 95%; -3.8 to 0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	VX-371 + Hypertonic Saline, VX-371 + Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4962
	Comments
	Method	Mixed-effects Model for Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 95%; -1.7 to 3.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Plasma Concentrations of VX-371
Time Frame	Pre-dose (90 minutes prior inhaled study drug administration) and 60 minutes post-dose on Days 1, 14 and 28 within treatment period 1 and 2

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of VX-371. Here, "overall number of participants analyzed" signifies participants evaluable for this outcome measure and "number analyzed" signifies those participants who were evaluable at specified time points.

Arm/Group Title	VX-371 + Hypertonic Saline	VX-371 + Placebo
Arm/Group Description	Participants received 85 mcg VX-371 diluted in 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.	Participants received 85 mcg VX-371 diluted in 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.
Measure Participants	89	45
Day 1: Pre-dose	0.00 (0.00)	0.18 (1.17)
Day 1: Post-dose	2.57 (2.35)	5.64 (4.27)
Day 14: Pre-dose	1.63 (3.06)	2.77 (4.77)
Day 14: Post-dose	5.81 (5.44)	11.0 (9.74)
Day 28: Pre-dose	2.68 (4.75)	3.67 (5.59)
Day 28: Post-dose	6.41 (6.92)	10.9 (9.48)

4. Secondary Outcome

Title	Urine Concentrations of VX-371
Time Frame	Pre-dose (90 minutes prior inhaled study drug administration) and 60 minutes post-dose on Days 1, 14 and 28 within treatment period 1 and 2

Outcome Measure Data

Analysis Population Description

The PK analysis set included all participants who received at least 1 dose of VX-371. Here, "overall number of participants analyzed" signifies participants evaluable for this outcome measure and "number analyzed" signifies those participants who were evaluable at specified time points.

Arm/Group Title	VX-371 + Hypertonic Saline	VX-371 + Placebo
Arm/Group Description	Participants received 85 mcg VX-371 diluted in 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.	Participants received 85 mcg VX-371 diluted in 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.
Measure Participants	88	45
Day 1: Pre-dose	0.0745 (0.699)	0.00 (0.00)
Day 1: Post-dose	7.78 (11.8)	22.1 (38.4)
Day 14: Pre-dose	41.0 (97.2)	69.6 (107)
Day 14: Post-dose	38.9 (64.8)	75.0 (98.7)
Day 28: Pre-dose	65.3 (155)	98.6 (175)
Day 28: Post-dose	49.1 (120)	75.1 (108)

Adverse Events

Time Frame	Baseline up to 28 days post last administration of study drug, up to 112 days
Adverse Event Reporting Description	Safety set included all participants who received at least 1 dose of inhaled study drug.
Arm/Group Title	VX-371 + Hypertonic Saline		Hypertonic Saline		VX-371 + Placebo		Placebo
Arm/Group Description	Participants received 85 mcg VX-371 diluted in 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.		Participants received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.		Participants received 85 mcg VX-371 diluted in 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.		Participants received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.
All Cause Mortality
	VX-371 + Hypertonic Saline		Hypertonic Saline		VX-371 + Placebo		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/89 (0%)		0/90 (0%)		0/46 (0%)		0/42 (0%)
Serious Adverse Events
	VX-371 + Hypertonic Saline		Hypertonic Saline		VX-371 + Placebo		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/89 (9%)		4/90 (4.4%)		6/46 (13%)		3/42 (7.1%)
Congenital, familial and genetic disorders
Cystic fibrosis related diabetes	1/89 (1.1%)		0/90 (0%)		0/46 (0%)		0/42 (0%)
Gastrointestinal disorders
Small intestinal obstruction	0/89 (0%)		1/90 (1.1%)		0/46 (0%)		0/42 (0%)
Infections and infestations
Infective pulmonary exacerbation of cystic	3/89 (3.4%)		3/90 (3.3%)		5/46 (10.9%)		3/42 (7.1%)
Investigations
Alanine aminotransferase increased	1/89 (1.1%)		0/90 (0%)		0/46 (0%)		0/42 (0%)
Aspartate aminotransferase increased	1/89 (1.1%)		0/90 (0%)		0/46 (0%)		0/42 (0%)
Blood creatine phosphokinase increased	1/89 (1.1%)		0/90 (0%)		0/46 (0%)		0/42 (0%)
Reproductive system and breast disorders
Testicular torsion	1/89 (1.1%)		0/90 (0%)		0/46 (0%)		0/42 (0%)
Respiratory, thoracic and mediastinal disorders
Bronchospasm	1/89 (1.1%)		0/90 (0%)		0/46 (0%)		0/42 (0%)
Haemoptysis	0/89 (0%)		2/90 (2.2%)		1/46 (2.2%)		0/42 (0%)
Surgical and medical procedures
Cystic fibrosis respiratory infection	1/89 (1.1%)		0/90 (0%)		0/46 (0%)		0/42 (0%)
Other (Not Including Serious) Adverse Events
	VX-371 + Hypertonic Saline		Hypertonic Saline		VX-371 + Placebo		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	49/89 (55.1%)		55/90 (61.1%)		26/46 (56.5%)		20/42 (47.6%)
Gastrointestinal disorders
Diarrhoea	5/89 (5.6%)		4/90 (4.4%)		2/46 (4.3%)		1/42 (2.4%)
Nausea	2/89 (2.2%)		3/90 (3.3%)		3/46 (6.5%)		0/42 (0%)
Vomiting	1/89 (1.1%)		6/90 (6.7%)		1/46 (2.2%)		0/42 (0%)
General disorders
Pyrexia	1/89 (1.1%)		5/90 (5.6%)		5/46 (10.9%)		5/42 (11.9%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	8/89 (9%)		12/90 (13.3%)		6/46 (13%)		3/42 (7.1%)
Nasopharyngitis	0/89 (0%)		5/90 (5.6%)		2/46 (4.3%)		2/42 (4.8%)
Investigations
Alanine aminotransferase increased	3/89 (3.4%)		5/90 (5.6%)		0/46 (0%)		4/42 (9.5%)
Pulmonary function test decreased	0/89 (0%)		0/90 (0%)		3/46 (6.5%)		0/42 (0%)
Nervous system disorders
Headache	6/89 (6.7%)		8/90 (8.9%)		2/46 (4.3%)		1/42 (2.4%)
Respiratory, thoracic and mediastinal disorders
Cough	20/89 (22.5%)		13/90 (14.4%)		13/46 (28.3%)		5/42 (11.9%)
Oropharyngeal pain	8/89 (9%)		6/90 (6.7%)		4/46 (8.7%)		1/42 (2.4%)
Nasal congestion	7/89 (7.9%)		5/90 (5.6%)		2/46 (4.3%)		1/42 (2.4%)
Respiration abnormal	7/89 (7.9%)		6/90 (6.7%)		3/46 (6.5%)		2/42 (4.8%)
Wheezing	6/89 (6.7%)		2/90 (2.2%)		0/46 (0%)		1/42 (2.4%)
Haemoptysis	5/89 (5.6%)		6/90 (6.7%)		5/46 (10.9%)		5/42 (11.9%)
Sputum increased	5/89 (5.6%)		2/90 (2.2%)		5/46 (10.9%)		2/42 (4.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.